Immune Checkpoint Inhibitor-associated Myocarditis Research Articles

Mediators and mechanisms of immune checkpoint inhibitor-associated myocarditis: Insights from mouse and human.

The broad application of immune checkpoint inhibitors (ICIs) has led to significant gains in cancer outcomes. By abrogating inhibitory signals, ICIs promote T cell targeting of cancer cells but can frequently trigger autoimmune manifestations, termed immune-related adverse events (irAEs), affecting essentially any organ system. Among cardiovascular irAEs, immune-related myocarditis (irMyocarditis) is the most described and carries the highest morbidity. The currently recommended treatment for irMyocarditis is potent immunosuppression with corticosteroids and other agents, but this has limited evidence basis. The cellular pathophysiology of irMyocarditis remains poorly understood, though mouse models and human data have both implicated effector CD8+ T cells, some of which are specific for the cardiomyocyte protein α-myosin. While the driving molecular signals and transcriptional programs are not well defined, the involvement of chemokine receptors such as CCR5 and CXCR3 has been proposed. Fundamental questions regarding why only approximately 1% of ICI recipients develop irMyocarditis and why irMyocarditis carries a much worse prognosis than other forms of lymphocytic myocarditis remain unanswered. Further work in both murine systems and with human samples are needed to identify better tools for diagnosis, risk-stratification, and treatment.

Knowledge gaps and educational needs for common cancer therapy-related cardiovascular toxicities and related drug interactions.

e13672 Background: Unprecedented growth in novel oncolytic agents has led to an increase in the complexity of cancer management, including cancer therapy-related cardiovascular toxicities (CTR-CVTs) and related pharmacodynamic (PD) and pharmacokinetic (PK) drug-drug interactions (DDIs). The intent of this survey is to assess the landscape of CTR-CVTs including health care provider (HCP) educational needs. Methods: A 20-question survey was distributed to HCPs primarily specializing in cardiology, oncology, hematology and cardio-oncology. The survey was distributed on email listservs of targeted organizations, including the International Cardio-Oncology Society. In addition to demographics, the survey assessed CTR-CVTs and related DDIs encountered. Perceived knowledge gaps were also assessed. Data was analyzed and summarized utilizing descriptive statistics. Results: Of 220 survey respondents, 46% were pharmacists and 54% were other HCPs ( > 80% physicians). Respondents predominately practiced in North America (59%) or Europe (20%), with the majority at academic medical centers (65% academic, 35% community) and primarily specializing in cardiology (71%, cardiology, 26% oncology, 14% hematology). Types of malignancies managed were primarily solid tumors (74%), however hematological malignancy management was also common ( > 60%). All HCPs reported encountering the following CTR-CVTs most commonly: cancer therapy-related cardiac dysfunction (CTRCD) (88%), hypertension (HTN) (79%) and thromboembolic disease (71%). Overall, pharmacists reported managing CTR-CVTs less frequently than other HCPs, especially regarding atrial fibrillation/flutter, coronary artery disease/vasospasm and bradycardia/AV block. The most common cardio-oncology-related PD DDIs encountered were CTRCD and QT prolongation/Torsades de Pointes (QTP/TdP). The most frequently managed cardio-oncology-related PK DDIs included antiarrhythmic agents, direct-acting oral anticoagulants and antiplatelet agents. All HCPs reported greatest comfort managing anthracycline/HER2 targeted therapy-associated CTRCD and least comfort managing arsenic-associated QTP. Immune checkpoint inhibitor-associated myocarditis (74%), immune modulator-associated thrombosis/thrombotic events (64%), Bruton tyrosine kinase inhibitor associated bleeding (58%) and atrial fibrillation (55%) were ranked of highest educational need. Overall, responses for PD/PK DDIs and educational recommendations were similar between pharmacists and other HCPs. Conclusions: This survey provides insight on the most commonly encountered CTR-CVTs and related DDIs as well as knowledge gaps of HCPs managing CTR-CVTs. These specific areas should be targeted for future educational initiatives to optimize the cardiovascular care of patients with cancer.

Diagnostic value of the International Society of Cardio-Oncology (IC-OS) definition for suspected immune checkpoint inhibitor-associated myocarditis

The diagnosis of immune checkpoint inhibitor-associated myocarditis (ICI-M) is challenging. Recently, the International Society of Cardio-Oncology (IC-OS) proposed an empirical definition of ICI-M; however, this definition has never been validated. We aimed to assess the diagnostic value at admission of the IC-OS definition in a cohort of patients with suspected ICI-M and to determine whether the addition of other criteria to this definition would improve its performance. Between May 2017 and November 2021, all patients with suspected ICI-M were consecutively included in a multicenter cohort. The final diagnosis was the one recorded in the patient's electronic medical record, established within one month of hospital discharge by the expert cardio-oncology team that managed the patient. Of the 68 patients included, 45 patients presented with ICI-M. The sensitivity, specificity, and positive and negative likelihood ratios of the IC-OS definition were 93% (95% CI: 82%–99%), 70% (95% CI: 47%–87%), 3.1 (95% CI: 1.7–5.7), and 0.1 (95% CI: 0–0.3), respectively. A delay in the onset of the first events < 3 months after the introduction of ICIs was the only variable that was both significantly associated with the final diagnosis of ICI-M and did not already meet the criteria of the IC-OS definition (72% vs. 52%, P = 0.03). By including this variable as a new minor criterion and increasing the number of minor criteria for defining ICI-M to 3, the specificity increased from 70% to 83% (P = 0.08), and the sensitivity remained unchanged (93%). The IC-OS definition for the diagnosis of ICI-M showed excellent sensitivity and moderate specificity. The latter could be increased by a modified definition including the time of the onset of the first events < 3 months after the introduction of ICIs (Fig. 1).

Early evaluation of severe immune checkpoint inhibitor-associated myocarditis: a real-world clinical practice.

Immune checkpoint inhibitor (ICI)-associated myocarditis is a rare but severe complication for patients treated with immunotherapy. This study aims to explore the predictive significance of patients' clinical features and examination results for the severity of ICI-associated myocarditis. Data from a real-world cohort of 81 cancer patients who developed ICI-associated myocarditis after immunotherapy were retrospectively analyzed. The development of myocarditis of Common Terminology Criteria for Adverse Events (CTCAE) grades 3-5 and/or the major adverse cardiovascular event (MACE) was set as endpoints. Logistic regression was used to evaluate the predictive value of each factor. CTCAE grades 3-5 and MACE developed in 43/81 (53.1%) and 28/81 (34.6%) cases, respectively. The likelihood of CTCAE grades 3-5 and MACE increased with the accumulation of organs affected by the ICI-associated adverse events and initial clinical symptoms. Concurrent systematic therapies during ICI treatment did not raise the risk of myocarditis severity, while prior chemotherapy did. Besides classical serum cardiac markers, a higher neutrophil ratio was also related to poorer cardiac outcomes, whereas higher lymphocyte and monocyte ratios were predictors of favorable cardiac outcomes. The CD4+ T cell ratio and CD4/CD8 ratio were negatively related to CTCAE grades 3-5. Several cardiovascular magnetic resonance parameters were associated with myocarditis severity, whereas the predictive value of echocardiography and electrocardiogram was weak. This study comprehensively evaluated the prognostic value of patients' clinical characteristics and examination results and identified several predictors of severe ICI-associated myocarditis, which will facilitate early detection of severe ICI-associated myocarditis in patients receiving immunotherapy.

A case of subclinical immune checkpoint inhibitor-associated myocarditis in non-small cell lung cancer

BackgroundImmune checkpoint inhibitors (ICIs) have been widely used in the treatment of cancer. Moreover, immune-related adverse events (irAEs) have become a new clinical challenge. ICI-associated myocarditis is a rare but fatal condition among diverse organ injuries, and early recognition and effective interventions are critical for patients.Case presentationIn this report, we present the case of a healthy 60-year-old male who was diagnosed with lung squamous cell carcinomas following chemotherapy and received ICIs. The patient presented with asymptomatic cardiac biomarker elevation followed by immune-related myocarditis. Fortunately, the patient achieved a good clinical result after receiving high-dose steroids. The treatment with ICIs was discontinued because of recurrent increases in troponin T.ConclusionICI-mediated associated myocarditis is an uncommon but potentially life-threatening adverse event. The current data suggest that clinicians need to be cautious about reinitiation in low-grade patients; however, further study of the diagnosis and treatment is necessary.

Clinicopathological classification of immune checkpoint inhibitor-associated myocarditis: possible refinement by measuring macrophage abundance

BackgroundImmune checkpoint inhibitor (ICI) myocarditis is associated with high morbidity and mortality. While endomyocardial biopsy (EMB) is considered a gold standard for diagnosis, the sensitivity of EMB is not well defined. Additionally, the pathological features that correlate with the clinical diagnosis of ICI-associated myocarditis remain incompletely understood.MethodsWe retrospectively identified and reviewed the clinicopathological features of 26 patients with suspected ICI-associated myocarditis based on institutional major and minor criteria. Seventeen of these patients underwent EMB, and the histopathological features were assessed by routine hematoxylin and eosin (H&E) staining and immunohistochemical (IHC) staining for CD68, a macrophage marker.ResultsOnly 2/17 EMBs obtained from patients with suspected ICI myocarditis satisfied the Dallas criteria. Supplemental IHC staining and quantification of CD68+ macrophages identified an additional 7 patients with pathological features of myocardial inflammation (> 50 CD68+ cells/HPF). Macrophage abundance positively correlated with serum Troponin I (P = 0.010) and NT-proBNP (N-terminal pro-brain natriuretic peptide, P = 0.047) concentration. Inclusion of CD68 IHC could have potentially changed the certainty of the diagnosis of ICI-associated myocarditis to definite in 6/17 cases.ConclusionsWhile the Dallas criteria can identify a subset of ICI-associated myocarditis patients, quantification of macrophage abundance may expand the diagnostic role of EMB. Failure to meet the traditional Dallas Criteria should not exclude the diagnosis of myocarditis.

IMMUNE CHECKPOINT INHIBITOR ASSOCIATED MYOCARDITIS

IMMUNE CHECKPOINT INHIBITOR ASSOCIATED MYOCARDITIS

Immune Checkpoint Inhibitor-Associated Myocarditis: From Pathophysiology to Rechallenge of Therapy – a Narrative Review

Even if immunecheckpoint inhibitors have revolutionized the landscape of cancer therapy, their use may be complicated by immune-related adverse events. Among these, myocarditis is the most severe complication. The clinical suspicion often arises after clinical symptoms onset and increase in cardiac biomarkers or electrocardiographic manifestations. Echocardiography and cardiac magnetic resonance imaging are recommended for each patient. However, since they may be misleadingly normal, endomyocardial biopsy remains the gold standard for establishing the diagnosis. Until now, treatment has been based on glucocorticoids even if increasing interest has risen in other immunosuppressive agents. Although myocarditis currently imposes immunotherapy discontinuation, case reports have suggested a safety rechallenge in low-grade myocarditis paving the way for further studies to respond to this unmet clinical need.

Fulminant Myocarditis Complicated with Immune Checkpoint Inhibitor in Patients with Thymoma: Report of Three Cases

: Immune checkpoint inhibitors (ICIs) prevent the immune escape of tumor cells, which helps immune cells such as T lymphocytes to continuously monitor and kill tumor cells, and play powerful anti-tumor role. Immune checkpoint inhibitor-associated myocarditis has been rarely reported; however, its latent, rapidly developed, and lethal onset has gradually attracted the attention of clinicians. This study aimed to report cases of fulminant myocarditis in three patients with thymoma who were treated with pembrolizumab, one of the programmed cell death protein 1 inhibitors (PD-1 inhibitors).

Multi-organ Immune-Related Adverse Event Is a Risk Factor of Immune Checkpoint Inhibitor-Associated Myocarditis in Cancer Patients: A Multi-center Study.

Background and ObjectiveImmune checkpoint inhibitor (ICI)-associated myocarditis is a fatal immune-related adverse events (irAEs), which is prone to affecting multiple organ systems. Multi-organ irAEs have not been fully studied in ICI-associated myocarditis. Therefore, we aimed to explore the impact of multi-organ irAEs on ICI myocarditis in terms of clinical features, treatment, and prognosis.MethodsThis was a retrospective study. The clinical data of ICI myocarditis patients were collected from 6 hospitals in China. The risk factors and characteristics of pure myocarditis and multi-organ irAEs were analyzed. The overall survival (OS) after myocarditis was analyzed and univariate and multivariate regression analysis were performed.ResultsA total of 46 patients were analyzed in this study. Multi-organ irAEs were common (30/46, 65.2%) and prone to severe heart failure. The severe myocarditis was observed in 32 patients (69.6%). When myocarditis occurred, neutrophil to lymphocyte ratio, C-reactive protein, lactate dehydrogenase, interleukin (IL)-6, IL-10, creatine kinase, MB isoenzyme of creatine kinase, and brain natriuretic peptide increased from baseline, but absolute lymphocyte count decreased. Thymoma (B2/B3) was a risk factor for multi-organ irAEs. Heart failure and myocarditis were more severe in patients with multi-organ irAEs and require early corticosteroid therapy (<24 hours). Univariate analysis showed that age ≥ 60 years, myocarditis (grade 3-4), heart failure (grade 3-4), multi-organ irAEs, and severe myocarditis were associated with OS after myocarditis. After adjusting for other factors, heart failure (grade 3-4) was an independent risk factor for immune-related myocarditis (HR: 6.655, 95% CI: 1.539-28.770, p=0.011).ConclusionPatients with ICI-associated myocarditis had multi-organ irAEs with a high incidence of severe myocarditis, mortality, and poor prognosis. Thymoma was prone to those patients with multiple organs involvement. Patients could benefit from early corticosteroid intervention. Heart failure (grade 3-4) was an independent risk factor for OS after myocarditis.

Single-cell profiling of human heart and blood in immune checkpoint inhibitor-associated myocarditis.

2507 Background: Myocarditis due to immune checkpoint inhibitors (ICIs) is uncommon; however, myocarditis due to ICIs leads to severe morbidity and even death in 20-40% of cases. The molecular underpinnings of ICI-associated myocarditis are poorly understood, and there is an unmet clinical need to identify therapeutic targets and biomarkers that can aid in disease management. Methods: Heart tissue was obtained through endomyocardial biopsy or autopsy of patients receiving ICIs and was profiled with paired single-cell RNA sequencing (scRNA-seq) and T cell receptor sequencing (TCR) using the 10x Genomics Chromium system. A control dataset was constructed using scRNAseq data of heart tissue from patients receiving ICIs but without myocarditis and a published dataset from healthy patients not receiving ICIs. Peripheral blood mononuclear cells (PBMCs) were collected at the time of myocarditis diagnosis in a larger cohort of patients and analyzed with ICI-treated controls. The CITE-Seq protocol was used to measure paired scRNA-seq, TCR, and surface proteomics in PBMCs, using serial timepoints where available. Results: Heart tissue from 13 patients with myocarditis, including three fatal cases, and seven controls yielded 77,712 single cells. Blood profiling from 27 patients with ICI myocarditis and ICI-treated controls across 54 samples yielded over 230,000 cells. ICI myocarditis tissue demonstrated an increased T cell infiltrate (OR 8.94, FDR = 0.0021). Expression of multiple inflammatory pathways, most notably interferon responses, was up-regulated across multiple immune and non-immune cell types in the setting of myocarditis, providing important pathophysiological insights. T cell clones were also found to be shared between blood and heart, enabling the identification of putative pathogenic T cell subsets. Conclusions: Increased intramyocardial T cells and the activation of interferon response gene networks were seen in the setting of ICI myocarditis. These preliminary findings highlight potential pathological pathways in ICI myocarditis that could serve as biomarkers or therapeutic targets.

Association of early electrical changes with cardiovascular outcomes in immune checkpoint inhibitor myocarditis

Immune-checkpoint inhibitor-associated myocarditis (ICI-myocarditis) often presents with arrhythmias, but the prognostic value of early electrocardiogram findings is unclear. Although ICI-myocarditis and acute cellular rejection (ACR) following cardiac transplantation use similar treatment strategies, differences in arrhythmia burden are unknown. To evaluate the association of electrocardiogram findings in ICI-myocarditis with myocarditis-related mortality and life-threatening arrhythmia. A total of 125 cases of ICI-myocarditis were identified retrospectively across 49 hospitals worldwide; 50 cases of grade 2R or 3R ACR were included as comparators. Two cardiologists blinded to clinical data interpreted electrocardiograms. Associations between electrocardiogram features, myocarditis-related mortality and the composite of myocarditis-related mortality and life-threatening arrhythmias were examined. Adjusted hazard ratios (aHRs) were calculated. The cohort had 78 (62.4%) men; median (interquartile range) age was 67 (58-76) years. At 30 days, myocarditis-related mortality was 20/124 (16.1%), and 28/124 (22.6%) met the composite endpoint. Patients who developed complete heart block (aHR by subdistribution hazards model [aHR(sh)] 3.29, 95% confidence interval [CI] 1.24-8.68; P=0.02) or life-threatening cardiac arrhythmias (aHR(sh) 6.82, 95% CI: 2.87-16.21; P<0.001) had a higher risk of myocarditis-related mortality. Pathological Q waves (aHR(sh) 3.40, 95% CI: 1.38-8.33; P=0.008), low QRS voltage (aHR(sh) 6.05, 95% CI: 2.10-17.39; P<0.001) and Sokolow-Lyon index (aHR(sh)/mV 0.54, 95% CI: 0.30-0.97; P=0.04) on admission electrocardiogram were also associated with increased risk of myocarditis-related mortality. These associations were mirrored in the composite outcome analysis. Compared with ACR, ICI-myocarditis had a higher incidence of life-threatening cardiac arrhythmias (15/125 [12.0%] vs 1/50 [2%]; P=0.04) and third-degree heart block (19/125 [15.2%] vs 0/50 [0%]; P=0.004). Electrocardiograms in ICI-myocarditis with ventricular tachycardias, heart block, low-voltage and pathological Q waves were associated with myocarditis-related mortality and life-threating arrhythmia. Arrhythmia burden in ICI-myocarditis exceeds that of ACR after heart transplant.

Sick Sinus Syndrome: More Than a Needle-in-a-haystack Manifestation of Immune Checkpoint Inhibitor-associated Myocarditis.

Sick Sinus Syndrome: More Than a Needle-in-a-haystack Manifestation of Immune Checkpoint Inhibitor-associated Myocarditis.

Immune checkpoint inhibitor-associated myocarditis : Case reports and areview of the literature.

Immune checkpoint inhibitors (ICIs) are increasingly recognised to effectuate long-lasting therapeutic responses in solid tumours. However, ICI therapy can also result in various immune-related adverse events, such as ICI-associated myocarditis, a rare but serious complication. The clinical spectrum is wide and includes asymptomatic patients and patients with fulminant heart failure, making it challenging to diagnose this condition. Furthermore, the optimal diagnostic algorithm and treatment of ICI-associated myocarditis is unknown. In this review, we describe two cases on both ends of the spectrum and discuss the challenges in recognising, diagnosing and treating ICI-associated myocarditis.

免疫チェックポイント阻害剤関連心筋炎の新規病態モデル開発

免疫チェックポイント阻害剤関連心筋炎の新規病態モデル開発

Clinical characteristics, time course, treatment and outcomes of patients with immune checkpoint inhibitor-associated myocarditis

BackgroundImmune checkpoint inhibitors (ICI) have emerged as a front-line therapy for a variety of solid tumors. With the widespread use of these agents, immune-associated toxicities are increasingly being recognized, including...

ECHOCARDIOGRAPHIC FEATURES OF IMMUNE CHECKPOINT INHIBITOR ASSOCIATED MYOCARDITIS AND THEIR ASSOCIATION WITH ADVERSE OUTCOMES

ECHOCARDIOGRAPHIC FEATURES OF IMMUNE CHECKPOINT INHIBITOR ASSOCIATED MYOCARDITIS AND THEIR ASSOCIATION WITH ADVERSE OUTCOMES

Autoimmunity against Cardiac Self-Antigen Drives Immune Checkpoint Inhibitor-Associated Myocarditis Development

Abstract Immune checkpoint inhibitor (ICI) blocking PD-1 has been approved by the Food and Drug Administration for treatment of several types of cancers. However, fulminant myocarditis has occurred in the ICI-treated cancer patients, with low incidence but with 50 percent mortality. In this study, we investigated if PD-1 blockade can induce myocarditis in the mouse mimicking ICI-associated myocarditis in the human. We found that anti-PD-1 mAb treatment caused myocarditis development in A/J mice exhibiting enlarged heart and increased cardiac infiltration. In the cardiac infiltration, CD8+ T cells, CD4+ T cells, monocytes and macrophages were increased in the PD-1 blockade group compared to isotype control. Cardiac damage was confirmed by elevated serum level of cardiac troponin I and anti-myosin IgG. In addition, PD-1 blockade caused arrhythmia, right bundle branch block, while controls showed a normal ECG trace. The A/J mice with PD-1 blockade also developed systemic autoimmune responses such as colitis, sialadenitis, pneumonitis and myositis like immune-related adverse events in the human, supporting the immunotoxicity of PD-1 blockade. Next, using myosin-MHC tetramer staining, we found the increase of autoreactive T cells specific for cardiac myosin in the mouse heart with ICI-associated myocarditis compared to control. In the naïve heart, we were able to detect myosin-specific T cells, which number was very few but expressed a high level of PD-1. Collectively, we have developed the mouse model for human ICI-associated myocarditis and showed that the pathogenesis of this disease is an autoimmune reaction against heart-specific antigens.

Immune checkpoint inhibitor-associated myocarditis: manifestations and mechanisms.

Immune checkpoint inhibitors (ICIs) have transformed the treatment of various cancers, including malignancies once considered untreatable. These agents, however, are associated with inflammation and tissue damage in multiple organs. Myocarditis has emerged as a serious ICI-associated toxicity, because, while seemingly infrequent, it is often fulminant and lethal. The underlying basis of ICI-associated myocarditis is not completely understood. While the importance of T cells is clear, the inciting antigens, why they are recognized, and the mechanisms leading to cardiac cell injury remain poorly characterized. These issues underscore the need for basic and clinical studies to define pathogenesis, identify predictive biomarkers, improve diagnostic strategies, and develop effective treatments. An improved understanding of ICI-associated myocarditis will provide insights into the equilibrium between the immune and cardiovascular systems.

Using Natural Language Processing to Identify Patients with Immune Checkpoint Inhibitor-Associated Myocarditis

Using Natural Language Processing to Identify Patients with Immune Checkpoint Inhibitor-Associated Myocarditis